Prolonged microgravity exposure during long-duration spaceflight (LDSF) produces unusual physiologic and pathologic neuro-ophthalmic findings in astronauts. These microgravity-associated findings collectively define the Spaceflight Associated Neuro-ocular Syndrome (SANS). In this book, the editors compare and contrast prior published work on SANS by the National Aeronautics and Space Administration’s (NASA) Space Medicine Operations Division with retrospective and prospective studies from other research groups. The book describes the possible mechanisms and potential etiologies for SANS, and provides an update and review on the clinical manifestations of SANS including: unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and focal areas of ischemic retina (i.e., cotton wool spots). The ocular imaging findings (e.g., retinal nerve fiber layer, optic disc, and choroidal changes on optical coherence tomography) of SANS is also described, including the intraorbital and intracranial findings on orbital ultrasound and magnetic resonance imaging. The knowledge gaps for in-flight and terrestrial human research including potential countermeasures for future stud is also explored, including reports on the in-flight and terrestrial human and animal research being investigated by NASA and its partners to study SANS both prospectively and longitudinally and in preparation for future long duration manned missions to space including the moon, the asteroid belt, or Mars. We think this is a unique topic and hope that NASA and its research partners continue to study SANS in preparation for future longer duration manned space missions.